Co-receptor signalling is an important mechanism for coordinating and tightly regulating immune responses. The usual scheme of activation of αβ T cells relies on positive signals given by peptide antigens presented by HLA class I or II. Co-receptor signals will either increase or prevent this activation.
Among the negative signalling molecules, those belonging to CD28/B7 families are by far the most studied. Three members of this family have been described: CTL-associated antigen-4 (CTLA-4), programmed death-1 (PD-1) and B and T lymphocyte attenuator (BTLA). They all play a role in the control of tolerance. They provide negative signals that limit, terminate and/or attenuate immune responses.
PD-1 was isolated as a gene up-regulated in a T cell hybridoma undergoing apoptosis and was named program death 1. PD-1 or CD279 is expressed on activated T and B cells as well as on activated myeloid cells.
Its expression is broader than CTLA-4 which is only found on activated T cells.
Upon coligation with the T cell Receptor (TcR), PD-1 elicits inhibitory signals.
The PD-1 cytoplasmic domain contains two tyrosines, one that constitutes an immunoreceptor tyrosine inhibitory receptor (ITIM) and the other one an immunoreceptor tyrosine based switch motif (ITSM). The phosphorylation of the second tyrosine leads to the recruitment of the tyrosine phosphatases SHP2 and to some extent SHP1. These phosphatases will dephosphorylate ZAP70, CD3ζ and PKC θ and consequently will attenuate T cell signals.
PD-1 mainly inhibits T and B cell proliferation by causing cell arrest in G0/G1 and inhibiting cytokine production in T cells.
Two PD-1 ligands have been described, PD-L1/B7H1/CD274 and PD-L2/B7-DC/CD273. PD-L1 is expressed at low levels on immune cells such as B cells, dendritic cells, macrophages and T cells and is up regulated following activation. PD-L1 is also expressed on non-lymphoid organs such as endothelial cells, heart, lung, pancreas, muscle, keratinocytes and placenta. The expression within non lymphoid tissues suggests that PD-L1 may regulate the function of self reactive T and B cells as well as myeloid cells in peripheral tissues or may regulate inflammatory responses in the target organs. PD-L1 expression is mainly regulated by type 1 and 2 interferon which are major regulators of PD-L1 on endothelial and epithelial cells. PD-L1 is expressed in tumor samples and is associated to poor prognosis. Various viral infections induce the intense PD-L1 expression on host tissues.
PD-L2/B7-DC cell surface expression is restricted to macrophages and dendritic cells, though PD-L2 transcript was found in non hematopietic tissues such as heart, liver and pancreas. Its surface expression depends on the production of IFNγ and Th2 cytokines.
PD-L1 and PD-L2 expression depends also on distinct stimuli. On macrophages PD-L1 is induced by INFy whereas PD-L2 is induced by IL-4. A similar regulation is found on DC though these differences are not absolute. These studies tend to suggest that PD-L1 might regulate preferentially Th1 responses whereas PD-L2 would regulate Th2 responses.
Both PD-L1 and PD-L2 inhibit T cell proliferation, cytokine production and β1 and β2 integrins mediated adhesion. Although some contradictory data have proposed a costimulatory function. However, PD-L2 but not PD-L1 triggers reverse signalling in dendritic cells leading to IL-12 production and activation of T cells.
The expression patterns of PD-L1 and PD-L2 suggest both overlapping and differential roles in immune regulation. PD-L1 is abundant in a variety of human cancers (Dong et al (2002) Nat. Med. 8:787-9). The interaction between PD-1 and PD-L1 results in a decrease in tumor infiltrating lymphocytes, a decrease in T-cell receptor mediated proliferation, and immune evasion by the cancerous cells (Dong et al. (2003) J. MoI. Med. 81:281-7; Blank et al. (2005) Cancer Immunol. Immunother. 54:307-314; Konishi et al. (2004) Clin. Cancer Res. 10:5094-100) Immune suppression can be reversed by inhibiting the local interaction of PD-1 with PD-L1, and the effect is additive when the interaction of PD-1 with PD-L2 is blocked as well (Iwai et al. (2002) Proc. Nat. 7. Acad. ScL USA 99: 12293-7; Brown et al. (2003) J. Immunol. 170:1257-66).
PD-1 deficient animals develop various autoimmune phenotypes, including autoimmune cardiomyopathy and a lupus-like syndrome with arthritis and nephritis (Nishimura et al. (1999) Immunity H: 141-51; Nishimura et al. (2001) Science 291:319-22). Additionally, PD-1 has been found to play a role in autoimmune encephalomyelitis, systemic lupus erythematosus, graft-versus-host disease (GVHD), type I diabetes, and rheumatoid arthritis (Salama et al. (2003) J Exp Med 198:71-78: Prokunina and Alarcon-Riquelme (2004) Hum MoI Genet. 13:R143; Nielsen et al. (2004) Lupus 11:510).
In animal models, PD-L1 and PD-L2 blockade using blocking mAbs evidence distinct roles in the susceptibility and chronic progression of experimental autoimmune encephalitis in a strain specific manner. In NOD prediabetic mice PD-L1 but not PD-L2 blockade precipitated diabetes. Using the RIP-mOVA mouse model of autoimmune diabetes, Martin-Orozco et al. found that PD-L1 but not PD-L2 mediated the inhibition of diabetes onset (Martin-Orozco et al. (2006) J. Immunol. 15; 177(12):8291-5).
To date, no satisfactory approach has been proven to induce potent immune responses against vaccines, especially in cancer patients. Methods have yet to be devised to overcome the immunosuppressive mechanisms observed in cancer patients, and during chronic infections.
Treatment of autoimmune diseases and prevention of transplantation rejection in graft versus host diseases (GVHD) depends on immunosuppressive agents that have serious side effects, or are not always effective. New immunosuppressive agents are desired.